1. Field of the Invention
The present invention relates to dimeric epipodophyllotoxin glucoside derivatives, to their therapeutic anti-tumor use, and to pharmaceutical dosage forms containing these new agents.
2. Description of the Related Art
Etoposide (VP-16, Ia) and teniposide (VM-26, Ib) are clinically useful anticancer agents derived from the naturally occurring lignan, podophyllotoxin (II). The numbering system used for nomenclature purposes is shown in Formula II. Etoposide and teniposide are 4'-demethyl epipodophyllotoxin derivatives; epipodophyllotoxin being the epimer of podophyllotoxin at the 4-position. Etoposide and teniposide are active in the treatment of a variety of cancers including small cell lung cancer, non-lymphocytic leukemia, and non-seminomatous testicular cancer (AMA Drug Evaluation, 5th Edition, American Medical Association, 1983, Chicago, Ill., p. 1554-5). ##STR1##
It has been postulated that one of the mechanisms by which etoposide exerts its cytotoxic activity involves stablilizing a DNA-topoisomerase II complex leading eventually to DNA strand breaks. This type of action has also been observed for other antitumor agents, e.g. adriamycin, mitoxantrone, and m-AMSA which, unlike etoposide, are DNA intercalators. Dimeric forms of adriamycin, mitoxantrone, and the intercalating 9-aminoacridine portion of m-AMSA have been prepared as potential bis-intercalators for DNA. Podophyllotoxin derivative of formula III was reported in J. Pharm. Sci., 1983, 72:1158-61; however, this compound was inactive against P388 leukemia. ##STR2##